Spinocerebellar Ataxia 8 (ATXN8OS)
| Dred_ID | RD00047 |
| OMIM ID | 608768 |
| Disease name | Spinocerebellar Ataxia 8 |
| Alternative names | SCA8 |
| Category | Genetic diseases, Rare diseases, Neuronal diseases, Skin diseases, Eye diseases, Mental diseases, Ear diseases, Metabolic diseases, Fetal diseases, Liver diseases |
| Phenotype | NIH Rare Diseases: Spinocerebellar ataxia type 8 (SCA8) is an inherited neurodegenerative condition characterized by slowly progressive ataxia (problems with movement, balance, and coordination). This condition typically occurs in adulthood and usually progresses over decades. Common initial symptoms include dysarthria, slow speech, and trouble walking. Some affected individuals experience nystagmus and other abnormal eye movements. Life span is typically not shortened. This condition is inherited in an autosomal dominant manner, although not all individuals with abnormalities in the disease-causing gene will develop the disease (called reduced penetrance).
OMIM: SCA8 is a slowly progressive ataxia with disease onset typically occurring in adulthood. Onset ranges from age one to 73 years. The progression is typically over decades regardless of the age of onset. Common initial symptoms are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability; life span is typically not shortened. Some individuals present with nystagmus, dysmetric saccades and, rarely, ophthalmoplegia. Tendon reflex hyperreflexity and extensor plantar responses are present in some severely affected individuals. Life span is typically not shortened. |
| Miscellaneouse | OMIM： onset between 18 and 65 years sca8 is caused by bidirectional transcription on chromosome 13q21 involving complementary repeat expansion in atxn8 and atxn8-opposite strand normal alleles contain 15 to 50 repeats pathogenic alleles contain 71 to 1,300 repeats |
| Prevalence | N/A [source: MalaCards] |
| Inheritance | Autosomal dominant |
| Anticipation | Yes |
| Evidence | Strong |
| Gene symbol | ATXN8OS |
| Alias symbols | SCA8; KLHL1AS; NCRNA00003 |
| Gene name | ATXN8 opposite strand |
| Gene map locus | 13q21; chr13:70,078,918-70,171,738(+) |
| Ensembl Gene ID | ENSG00000230223 |
| Gene expression and Gene Ontology | BioGPS |
| Protein expression | Human Protein Atlas |
| Gene sequence | Sequence |
| Variation | ClinVar, dbSNP | Gene conservation | Gene Conservation from UCSC Genome Browser |
| Gene Description | This gene is an antisense transcript to the KLHL1 gene (homolog to the Drosophila KELCH gene); it does not itself appear to be protein coding. A TAC/TGC trinucleotide repeat expansion that is incorporated into this gene transcript, but not the KLHL1 transcript, causes spinocerebellar ataxia type 8. Presumably the expansion interferes with normal antisense function of this transcript. [provided by RefSeq, Oct 2008] |
| Repeat unit | CTG |
| Normal repeat copies | 15-34 |
| Pathogenic repeat copies | ≥90 |
| Gene | ATXN8OS |
| Repeat location | exon |
| Chromosome locus | chr13:70139384-70139431 (+) |
| Repeat conservation | Repeat Conservation from UCSC Genome Browser |
| Toxic cause | RNA |
| Possible toxicity | Daughters et al. (2009) presented evidence that the expanded CTG repeat in the ATXN8OS gene (603680.0001) is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. In brain tissue from humans and mice with SCA8, ATXN8OS mRNA containing the expanded repeat was found to accumulate as ribonuclear inclusions, or RNA foci, that colocalized with the RNA-binding protein MBNL1 (606516) in selected cerebellar cortical neurons in the brain. In Sca8 mice, genetic loss of Mbnl1 enhanced motor deficits, suggesting that loss of MBNL1 plays a role in SCA8 pathogenesis. In Sca8 mice and SCA8 human brains, sequestration of MBNL1 in RNA foci resulted in the dysregulation of downstream splicing patterns normally regulated by the CUGBP1 (601074)/MBNL1 pathway, including that of mouse GABA transporter-4 (GAT4, or SLC6A11; 607952). These changes in Gat4 were associated with loss of GABAergic inhibition in the granular cell layer. These data indicated that expanded CUG ATXN8OS mRNA transcripts can dysregulate gene pathways in the brain, similar to the mechanism involved in myotonic dystrophy (DM1; 160900), which is caused by a CTG repeat expansion in the 3-prime UTR of the DMPK gene (605377) on chromosome 19q13. Daughters et al. (2009) also suggested that the findings may have relevance for other mainly CAG repeat expansion disorders in which an expanded CTG repeat on the opposite stand may also have toxic effects. [By OMIM] |
| Pathway annotation | Reactome, KEGG |
| PMID | 21173221 |
| Authors | Zu T1, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MA, Nan Z, Forster C. |
| Title | Non-ATG-initiated translation directed by microsatellite expansions |
| Journal | Proc Natl Acad Sci USA. 108(1):260-5 |
| Year | 2011 |
| PMID | 19680539 |
| Authors | Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ, Swanson MS, Ranum LP. |
| Title | RNA gain-of-function in spinocerebellar ataxia type 8 |
| Journal | PLoS Genet.5(8):e1000600 |
| Year | 2009 |